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Zhao, Juanjuan ; Okamoto, Yasuo ; Asano, Yuya ; Ishimaru, Kazuhiro ; Aki, Sho ; Yoshioka, Kazuaki ; Takuwa, Noriko ; Wada, Takashi ; Inagaki, Yutaka ; Takahashi, Chiaki ; Nishiuchi, Takumi ; Takuwa, Yoh ; 安藝, 翔 ; 吉岡, 和晃 ; 多久和, 典子 ; 和田, 隆志 ; 髙橋, 智聡 ; 西内, 巧 ; 多久和, 陽
出版情報: PLoS ONE.  13  pp.e0197604-,  2018-05-21.  Public Library of Science
URL: http://hdl.handle.net/2297/00053881
概要: 金沢大学医薬保健研究域医学系<br />Idiopathic pulmonary fibrosis is a devastating disease with poor prognosis. The pathogenic role of t he lysophospholipid mediator sphingosine-1-phosphate and its receptor S1PR2 in lung fibrosis is unknown. We show here that genetic deletion of S1pr2 strikingly attenuated lung fibrosis induced by repeated injections of bleomycin in mice. We observed by using S1pr2 LacZ/+ mice that S1PR2 was expressed in alveolar macrophages, vascular endothelial cells and alveolar epithelial cells in the lung and that S1PR2-expressing cells accumulated in the fibrotic legions. Bone marrow chimera experiments suggested that S1PR2 in bone marrow–derived cells contributes to the development of lung fibrosis. Depletion of macrophages greatly attenuated lung fibrosis. Bleomycin administration stimulated the mRNA expression of the profibrotic cytokines IL-13 and IL-4 and the M2 markers including arginase 1, Fizz1/Retnla, Ccl17 and Ccl24 in cells collected from broncho-alveolar lavage fluids (BALF), and S1pr2 deletion markedly diminished the stimulated expression of these genes. BALF cells from bleomycin–administered wild-type mice showed a marked increase in phosphorylation of STAT6, a transcription factor which is activated downstream of IL-13, compared with saline–administered wild-type mice. Interestingly, in bleomycin–adminis-tered S1pr2 -/- mice, STAT6 phosphorylation in BALF cells was substantially diminished compared with wild-type mice. Finally, pharmacological S1PR2 blockade in S1pr2 +/+ mice alleviated bleomycin–induced lung fibrosis. Thus, S1PR2 facilitates lung fibrosis through the mechanisms involving augmentation of IL-13 expression and its signaling in BALF cells, and represents a novel target for treating lung fibrosis. © 2018 Zhao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 続きを見る
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Wang, Fei ; Okamoto, Yasuo ; Inoki, Isao ; Yoshioka, Kazuaki ; Du, Wa ; Qi, Xun ; Takuwa, Noriko ; Gonda, Koichi ; Yamamoto, Yasuhiko ; Ohkawa, Ryunosuke ; Nishiuchi, Takumi ; Sugimoto, Naotoshi ; Yatomi, Yutaka ; Mitsumori, Kunitoshi ; Asano, Masahide ; Kinoshita, Makoto ; Takuwa, Yoh
出版情報: The journal of clinical investigation.  120  pp.3979-3995,  2010-11-01.  American Society for Clinical Investigation
URL: http://hdl.handle.net/2297/25352
概要: 金沢大学医薬保健研究域医学系<br />Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid that has pleiotropic effects in a variety of cell types including ECs, SMCs, and macrophages, all of which are central to the development of atherosclerosis. It may therefore exert stimulatory and inhibitory effects on atherosclerosis. Here, we investigated the role of the S1P receptor S1PR2 in atherosclerosis by analyzing S1pr2–/– mice with an Apoe–/– background. S1PR2 was expressed in macrophages, ECs, and SMCs in atherosclerotic aortas. In S1pr2–/–Apoe–/– mice fed a high-cholesterol diet for 4 months, the area of the atherosclerotic plaque was markedly decreased, with reduced macrophage density, increased SMC density, increased eNOS phosphorylation, and downregulation of proinflammatory cytokines compared with S1pr2+/+Apoe–/– mice. Bone marrow chimera experiments indicated a major role for macrophage S1PR2 in atherogenesis. S1pr2–/–Apoe–/– macrophages showed diminished Rho/Rho kinase/NF-κB (ROCK/NF-κB) activity. Consequently, they also displayed reduced cytokine expression, reduced oxidized LDL uptake, and stimulated cholesterol efflux associated with decreased scavenger receptor expression and increased cholesterol efflux transporter expression. S1pr2–/–Apoe–/– ECs also showed reduced ROCK and NF-κB activities, with decreased MCP-1 expression and elevated eNOS phosphorylation. Pharmacologic S1PR2 blockade in S1pr2+/+Apoe–/– mice diminished the atherosclerotic plaque area in aortas and modified LDL accumulation in macrophages. We conclude therefore that S1PR2 plays a critical role in atherogenesis and may serve as a novel therapeutic target for atherosclerosis. 続きを見る
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Nazifi, Ehsan ; Wada, Naoki ; Yamaba, Minami ; Asano, Tomoya ; Nishiuchi, Takumi ; Matsugo, Seiichi ; Sakamoto, Toshio
出版情報: Marine Drugs.  11  pp.3124-3154,  2013-01-01.  Ocean University of China, MDPI
URL: http://hdl.handle.net/2297/36264
概要: Mycosporine-like amino acids (MAAs) are water-soluble UV-absorbing pigments, and structurally different MAAs have been i dentified in eukaryotic algae and cyanobacteria. In this study novel glycosylated MAAs were found in the terrestrial cyanobacterium Nostoc commune (N. commune). An MAA with an absorption maximum at 334 nm was identified as a hexose-bound porphyra-334 derivative with a molecular mass of 508 Da. Another MAA with an absorption maximum at 322 nm was identified as a two hexose-bound palythine-threonine derivative with a molecular mass of 612 Da. These purified MAAs have radical scavenging activities in vitro, which suggests multifunctional roles as sunscreens and antioxidants. The 612-Da MAA accounted for approximately 60% of the total MAAs and contributed approximately 20% of the total radical scavenging activities in a water extract, indicating that it is the major water-soluble UV-protectant and radical scavenger component. The hexose-bound porphyra-334 derivative and the glycosylated palythine-threonine derivatives were found in a specific genotype of N. commune, suggesting that glycosylated MAA patterns could be a chemotaxonomic marker for the characterization of the morphologically indistinguishable N. commune. The glycosylation of porphyra-334 and palythine-threonine in N. commune suggests a unique adaptation for terrestrial environments that are drastically fluctuating in comparison to stable aquatic environments. © 2013 by the authors. 続きを見る
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Fujita, Nozomi ; Nagata, Yuka ; Nishiuchi, Takumi ; Sato, Makoto ; Iwami, Masafumi ; Kiya, Taketoshi
出版情報: Current Biology.  23  pp.2063-2070,  2013-10-21. 
URL: http://hdl.handle.net/2297/36281
概要: Many insects exhibit stereotypic instinctive behavior [1-3], but the underlying neural mechanisms are not well understoo d due to difficulties in detecting brain activity in freely moving animals. Immediate early genes (IEGs), such as c-fos, whose expression is transiently and rapidly upregulated upon neural activity, are powerful tools for detecting behavior-related neural activity in vertebrates [4, 5]. In insects, however, this powerful approach has not been realized because no conserved IEGs have been identified. Here, we identified Hr38 as a novel IEG that is transiently expressed in the male silkmoth Bombyx mori by female odor stimulation. Using Hr38 expression as an indicator of neural activity, we mapped comprehensive activity patterns of the silkmoth brain in response to female sex pheromones. We found that Hr38 can also be used as a neural activity marker in the fly Drosophila melanogaster. Using Hr38, we constructed a neural activity map of the fly brain that partially overlaps with fruitless (fru)-expressing neurons in response to female stimulation. These findings indicate that Hr38 is a novel and conserved insect neural activity marker gene that will be useful for a wide variety of neuroethologic studies. © 2013 Elsevier Ltd. All rights reserved. 続きを見る
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Rahman M., Mamunur ; Rahman M., Azizur ; Maki, Teruya ; Nishiuchi, Takumi ; Asano, T. ; Hasegawa, Hiroshi
出版情報: Chemosphere.  pp.213-219,  2014-01-01.  Elsevier
URL: http://hdl.handle.net/2297/36287
概要: Iron (Fe) is one of the vital limiting factors for phytoplankton in vast regions of the contemporary oceans, notably the high nutrient low chlorophyll regions. Therefore, it is apparent to be acquainted with the Fe uptake strategy of marine phytoplankton under Fe-limited condition. In the present study, marine phytoplankton Prymnesium parvum was grown under Fe-deplete (0.0025 μM) and Fe-rich (0.05 μM) conditions, and proteomic responses of the organism to Fe conditions were compared. In sodium dodecyl sulfate (SDS) gel electrophoresis, 7 proteins (16, 18, 32, 34, 75, 82, and 116 kDa) were highly expressed under Fe-deplete condition, while one protein (23 kDa) was highly expressed under Fe-rich condition. These proteins were subjected to 2-dimensional gel electrophoresis (2-D DIGE) to differentiate individual proteins, and were identified by matrix-assisted laser desorption-ionization-time of flight-mass spectrometer (MALDI-TOF-MS) analysis. The results showed that under Fe-deplete condition P. parvum increases the biosynthesis of ATP binding cassette (ABC) transporters, flagellar associated protein (FAP), and Phosphoribosylaminoimidazole-succinocarboxamide synthase. These proteins are assumed to be involved in a number of cellular biochemical processes that facilitate Fe acquisition in phytoplankton. Under Fe-deplete condition, P. parvum increases the synthesis of ribulose biphosphate carboxylase (RuBisCo), malate dehydrogenase, and two Fe-independent oxidative stress response proteins, manganese superoxide dismutase (MnSOD) and Serine threonine kinase (STK). Thus, marine phytoplankton may change their Fe acquisition strategy by altering the biosynthesis of several proteins in order to cope with Fe-limitation. © 2013 Elsevier Ltd. All rights reserved. 続きを見る
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Katayama, Natsu   ; Kato, Masahiro   ; Nishiuchi, Takumi ; Yamada, Toshihiro
出版情報: Evolution and Development.  13  pp.333-342,  2011-07-01.  Wiley-Blackwell
URL: http://hdl.handle.net/2297/29200
概要: During embryogenesis in angiosperms, the embryonic shoot and root meristems are created at opposite poles of the embryo, establishing a vertical body plan. However, the aquatic eudicot family Podostemaceae exhibits an unusual horizontal body plan, which is attributed to the loss of embryonic shoot and root meristems. To infer the embryogenetic changes responsible for the loss of these meristems, we examined the embryogenesis of three podostemads with different meristem characters, that is, Terniopsis brevis with distinct shoot and root meristems, Zeylanidium lichenoides with reduced shoot and no root meristems, and Hydrobryum japonicum with no shoot and no root meristems. In T. brevis, as in other eudicots, the putative organizing center (OC) and L1 layer (= the epidermal cell layer) arose to generate a distinct shoot meristem initial, and the hypophysis formed the putative quiescent center (QC) of a root meristem. Z. lichenoides had a morphologically unrecognizable shoot meristem, because a distinct L1 layer did not develop, whereas the putative OC precursor arose normally. In H. japonicum, the vertical divisions of the apical cells of eight-cell embryo prevented putative OC initiation. In Z. lichenoides and H. japonicum, the putative QC failed to initiate because the hypophysis repeated longitudinal divisions during early embryogenesis. Based on their phylogenetic relationships, we infer that the conventional embryonic shoot meristem was lost in Podostemaceae via two steps, that is, the loss of a distinct L1 layer and the loss of the OC, whereas the loss of the embryonic root meristem occurred once by misspecification of the hypophysis. © 2011 Wiley Periodicals, Inc. 続きを見る
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Mamunur, Rahman M. ; Azizur, Rahman M. ; Maki, Teruya ; Nishiuchi, Takumi ; Asano, Tomoya ; Hasegawa, Hiroshi
出版情報: Chemosphere.  95  pp.213-219,  2014-01-01.  Elsevier
URL: http://hdl.handle.net/2297/36780
概要: Iron (Fe) is one of the vital limiting factors for phytoplankton in vast regions of the contemporary oceans, notably the high nutrient low chlorophyll regions. Therefore, it is apparent to be acquainted with the Fe uptake strategy of marine phytoplankton under Fe-limited condition. In the present study, marine phytoplankton Prymnesium parvum was grown under Fe-deplete (0.0025 μM) and Fe-rich (0.05 μM) conditions, and proteomic responses of the organism to Fe conditions were compared. In sodium dodecyl sulfate (SDS) gel electrophoresis, 7 proteins (16, 18, 32, 34, 75, 82, and 116. kDa) were highly expressed under Fe-deplete condition, while one protein (23. kDa) was highly expressed under Fe-rich condition. These proteins were subjected to 2-dimensional gel electrophoresis (2-D DIGE) to differentiate individual proteins, and were identified by matrix-assisted laser desorption-ionization-time of flight-mass spectrometer (MALDI-TOF-MS) analysis. The results showed that under Fe-deplete condition P. parvum increases the biosynthesis of ATP binding cassette (ABC) transporters, flagellar associated protein (FAP), and Phosphoribosylaminoimidazole-succinocarboxamide synthase. These proteins are assumed to be involved in a number of cellular biochemical processes that facilitate Fe acquisition in phytoplankton. Under Fe-deplete condition, P. parvum increases the synthesis of ribulose biphosphate carboxylase (RuBisCo), malate dehydrogenase, and two Fe-independent oxidative stress response proteins, manganese superoxide dismutase (MnSOD) and Serine threonine kinase (STK). Thus, marine phytoplankton may change their Fe acquisition strategy by altering the biosynthesis of several proteins in order to cope with Fe-limitation. © 2013 Elsevier Ltd. 続きを見る
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Nazifi, Ehsan ; Wada, Naoki ; Asano, Tomoya ; Nishiuchi, Takumi ; Iwamuro, Yoshiaki ; Chinaka, Satoshi ; Matsugo, Seiichi ; Sakamoto, Toshio
出版情報: Journal of Photochemistry and Photobiology B: Biology.  142  pp.154-168,  2015-01-01.  Elsevier
URL: http://hdl.handle.net/2297/40610
概要: Mycosporine-like amino acids (MAAs) are UV-absorbing pigments, and structurally unique glycosylated MAAs are found in th e terrestrial cyanobacterium Nostoc commune. In this study, we examined two genotypes of N. commune colonies with different water extract UV-absorption spectra. We found structurally distinct MAAs in each genotype. The water extract from genotype A showed a UV-absorbing spectrum with an absorption maximum at 335 nm. The extract contained the following compounds: 7-O-(β-arabinopyranosyl)-porphyra-334 (478 Da), pentose-bound shinorine (464 Da), hexose-bound porphyra-334 (508 Da) and porphyra-334 (346 Da). The water extract from genotype B showed a characteristic UV-absorbing spectrum with double absorption maxima at 312 and 340 nm. The extract contained hybrid MAAs (1050 Da and 880 Da) with two distinct chromophores of 3-aminocyclohexen-1-one and 1,3-diaminocyclohexen linked to 2-O-(β-xylopyranosyl)-β-galactopyranoside. A novel 273-Da MAA with an absorption maximum at 310 nm was also identified in genotype B. The MAA consisted of a 3-aminocyclohexen-1-one linked to a γ-aminobutyric acid chain. These MAAs had potent radical scavenging activities in vitro and the results confirmed that the MAAs have multiple roles as a UV protectant and an antioxidant relevant to anhydrobiosis in N. commune. The two genotypes of N. commune exclusively produced their own characteristic glycosylated MAAs, which supports that MAA composition could be a chemotaxonomic marker for the classification of N. commune. 続きを見る
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Nazifi, Ehsan ; Wada, Naoki ; Asano, Tomoya ; Nishiuchi, Takumi ; Iwamuro, Yoshiaki ; Chinaka, Satoshi ; Matsugo, Seiichi ; Sakamoto, Toshio
出版情報: Journal of Photochemistry and Photobiology B: Biology.  144  pp.75-,  2015-03-01.  Elsevier
URL: http://hdl.handle.net/2297/41348
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Hasegawa, Mizuho ; Imamura, Ryu ; Motani, Kou ; Nishiuchi, Takumi ; Matsumoto, Norihiko ; Kinoshita, Takeshi ; Suda, Takashi
出版情報: Journal of immunology.  182  pp.7655-7662,  2009-06-15.  American Association of Immunologists
URL: http://hdl.handle.net/2297/18477
概要: 金沢大学がん研究所<br />Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an adaptor molec ule that mediates inflammatory and apoptotic signals. Although the role of ASC in caspase-1-mediated IL-1beta and IL-18 maturation is well known, ASC also induces NF-kappaB activation and cytokine gene expression in human cells. In this study, we investigated the molecular mechanism and repertoire of ASC-induced gene expression in human cells. We found that the specific activation of ASC induced AP-1 activity, which was required for optimal IL8 promoter activity. ASC activation also induced STAT3-, but not STAT1-, IFN-stimulated gene factor 3- or NF-AT-dependent reporter gene expression. The ASC-mediated AP-1 activation was NF-kappaB-independent and primarily cell-autonomous response, whereas the STAT3 activation required NF-kappaB activation and was mediated by a factor that can act in a paracrine manner. ASC-mediated AP-1 activation was inhibited by chemical or protein inhibitors for caspase-8, caspase-8-targeting small-interfering RNA, and p38 and JNK inhibitors, but not by a caspase-1 inhibitor, caspase-9 or Fas-associated death domain protein (FADD) dominant-negative mutants, FADD- or RICK-targeting small-interfering RNAs, or a MEK inhibitor, indicating that the ASC-induced AP-1 activation is mediated by caspase-8, p38, and JNK, but does not require caspase-1, caspase-9, FADD, RICK, or ERK. DNA microarray analyses identified 75 genes that were induced by ASC activation. A large proportion of them was related to transcription (23%), inflammation (21%), or cell death (16%), indicating that ASC is a potent inducer of inflammatory and cell death-related genes. This is the first report of ASC-mediated AP-1 activation and the repertoire of genes induced downstream of ASC activation. 続きを見る